Abstract
Background: The polymorphism Arg16 in β2-adrenergic receptor (ADRB2) gene has been associated with an increased risk of exacerbations in asthmatic children treated with long-acting β2-agonists (LABA). However, it remains unclear whether this increased risk is mainly attributed to this single variant or the combined effect of the haplotypes of polymorphisms at codons 16 and 27. Objective: We assessed whether the haplotype analysis could explain the association between the polymorphisms at codons 16 (Arg16Gly) and 27 (Gln27Glu) in ADRB2 and risk of asthma exacerbations in patients treated with inhaled corticosteroids (ICS) plus LABA. Methods: The study was undertaken using data from 10 independent studies (n = 5903) participating in the multi-ethnic Pharmacogenomics in Childhood Asthma (PiCA) consortium. Asthma exacerbations were defined as asthma-related use of oral corticosteroids or hospitalizations/emergency department visits in the past 6 or 12 months prior to the study visit/enrolment. The association between the haplotypes and the risk of asthma exacerbations was performed per study using haplo.stats package adjusted for age and sex. Results were meta-analysed using the inverse variance weighting method assuming random-effects. Results: In subjects treated with ICS and LABA (n = 832, age: 3–21 years), Arg16/Gln27 versus Gly16/Glu27 (OR: 1.40, 95% CI: 1.05–1.87, I2 = 0.0%) and Arg16/Gln27 versus Gly16/Gln27 (OR: 1.43, 95% CI: 1.05–1.94, I2 = 0.0%), but not Gly16/Gln27 versus Gly16/Glu27 (OR: 0.99, 95% CI: 0.71–1.39, I2 = 0.0%), were significantly associated with an increased risk of asthma exacerbations. The sensitivity analyses indicated no significant association between the ADRB2 haplotypes and asthma exacerbations in the other treatment categories, namely as-required short-acting β2-agonists (n = 973), ICS monotherapy (n = 2623), ICS plus leukotriene receptor antagonists (LTRA; n = 338), or ICS plus LABA plus LTRA (n = 686). Conclusion and clinical relevance: The ADRB2 Arg16 haplotype, presumably mainly driven by the Arg16, increased the risk of asthma exacerbations in patients treated with ICS plus LABA. This finding could be beneficial in ADRB2 genotype-guided treatment which might improve clinical outcomes in asthmatic patients.
| Original language | English |
|---|---|
| Pages (from-to) | 1157-1171 |
| Number of pages | 15 |
| Journal | Clinical and Experimental Allergy |
| Volume | 51 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - Sept 2021 |
Bibliographical note
ACKNOWLEDGEMENTSThe authors gratefully acknowledge the dedication, commitment and
contribution of the patients, families, recruiters, health care providers and pharmacists participating in all the studies involved in the
PiCA consortium. In particular, the authors thank Sandra Salazar
for her support as the GALA II / SAGE study coordinator. Individual
cohorts were funded as follows: BREATHE was funded by Scottish
Enterprises Tayside, the Gannochy Trust, and the Perth and Kinross
Council, and Brighton and Sussex Medical School. ESTATe was supported by a grant from the Netherlands Organization for Health
Research and Development (ZonMw; priority for medicines for children, Grant/Award Number: 113201006). PAGES was funded by
The Chief Scientist Office (reference number: CZH/4/418). GALAII
was funded by the National Heart, Lung, and Blood Institute of
the National Institute of Health (NIH) grants R01HL117004 and
X01HL134589; study enrolment supported by the Sandler Family
Foundation, the American Asthma Foundation, the RWJF Amos
Medical Faculty Development Program, Harry Wm. and Diana V.
Hind Distinguished Professor in Pharmaceutical Sciences II and
the National Institute of Environmental Health Sciences grant
R01ES015794. SAGE was supported by the National Heart, Lung,
and Blood Institute of the National Institute of Health (NIH) grants
R01HL117004 and X01HL134589; study enrolment supported by
the Sandler Family Foundation, the American Asthma Foundation,
the RWJF Amos Medical Faculty Development Program, Harry
Wm. and Diana V. Hind Distinguished Professor in Pharmaceutical
Sciences II. This study was also funded by the award (AC15/00015)
funded by the Instituto de Salud Carlos III (ISCIII) through Strategic
Action for Health Research (AES) and European Community (EC)
within the Active and Assisted Living (AAL) Programme framework
and the SysPharmPedia grant from the ERACoSysMed 1st Joint
Transnational Call from the European Union under the Horizon 2020,
and Maria Pino-Yanes was supported by the Ramón y Cajal Program
(RYC-2015-17205) by the Spanish Ministry of Economy, Industry, and
Competitiveness. Natalia Hernandez-Pacheco was supported by a
fellowship (FI16/00136) from ISCIII and co-funded by the European
Social Funds from the European Union (ESF) “ESF invests in your
future. PACMAN was supported by an unrestricted grant from
GSK (part of a strategic alliance between GSK and Utrecht Institute
for Pharmaceutical Sciences (UIPS)). PASS was funded by the UK
Department of Health through the NHS Chair of Pharmacogenomics
and carried out at the National Institute for Health Research (NIHR),
Alder Hey Clinical Research Facility. In the SLOVENIA study, the authors acknowledge the financial support from the Slovenian Research
Agency (research core funding No. P3-0067) and the SysPharmPedia
grant, co-financed by the Ministry of Education, Science and Sport
of the Republic of Slovenia (contract number C3330-16-500106).
Dr. CHEW Fook Tim (Singapore) received grants from the Singapore
Ministry of Education Academic Research Fund, Singapore
Immunology Network, National Medical Research Council (NMRC)
(Singapore), and the Agency for Science Technology and Research
(A*STAR) (Singapore); Grant Numbers: N-154-000-038-001; R154-000-191-112; R-154-000-404-112; R-154-000-553-112;
R-154-000-565-112; R-154-000-630-112; R-154-000-A08-592; R154-000-A27-597; R-154-000-A91-592; R-154-000-A95-592; R154-
000-B99-114; BMRC/01/1/21/18/077; BMRC/04/1/21/19/315;
SIgN-06-006; SIgN-08-020; NMRC/1150/2008; H17/01/a0/008;
and APG2013/108. FollwMAGICS was founded by the German charity Atemwegsliga and the German Ministry of Science and Education,
grant Sysinflame (grant number 01ZX1306E).
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